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Chapter 6

SERO-NEGATIVE ARTHROPATHIES

These are a group of interrelated disorders that include Ankylosing spondylitis, Reiter's disease, Psoriatic arthritis and enteropathic arthropathy.

These disorders are characterized by the following:

-Absence of rheumatoid factor in their serum

-Associated with HLA- B 27 in about 80% of cases.

-Lack of rheumatoid nodules

-They have special pattern of joint involvement Ankylosing spondylitis is the classical example of seronegative spondylo-arthropathies.

Ankylosing spondylitis

Definition:

A chronic inflammatory condition affecting mainly young adult males. In fully developed state characterized by ankylosis of sacro-iliac joints, inflammatory arthritis of synovial joints of spine, and ossification of spinal ligaments.

Aetiology: The prime cause is not identified.

Incidence: 2-5 per 1000 of adult males.

Age: Commonest 15-30 years.

Sex: Male : Female    4:1

Genetic factor: Certainly present, identified by familial aggregation, ankylosing spondylitis occurs in relatives of patients 30 times more commonly than in the general population. HLA- B27 occurs in over 90% of patients with ankylosing spondylitis, 50% of 1^st -degree relatives.

Genito-urinary infection: A high incidence of prostatic infection has been found in A.S. when compared with controls. Also klebsiella pneumoniae in faecal flora, said to be associated with activity of A.S.

Immunological Mechanisms: Suggested by hypergamma-globulinaemia, IgG antiglobulins and HLA B27.

Clinical Features:

Onset: Insidious onset of low back pain in young male aged 15-25 ys is typical.

Types of presentation:

a)Low back pain: Classically, young male complains of low back pain of gradual onset, worse at night, and stiffness on rising in morning. Pain often radiates to buttocks and backs of thighs, improves with exercises (unlike mechanical back pain) and not with rest. Accompanied by morning stiffness involving spine.

b)Persistent aching and stiffness in:

- Lower back

- Buttocks

- Back and sides of upper thighs

- Worst in the morning and after inactivity, relieved by exercise and not with rest unlike mechanical low back pain.

Symptoms:

- Symptoms may be episodic initially.

- Gradual progression of spinal symptoms may spread to:

       Costo-chondral joints.    Girdle joints large limb joints.

- A typical onset may be in limb joint.

- Iritis may be a presenting feature.

Signs:

-Initial findings are features of sacroilitis, marked loss of spinal movement, especially extension, and lateral movement, loss of normal lumbar lordosis.

-Focal point of tenderness around pelvic rim, sternum, heel & ischial tuberosities.

-Chest expansion of less than 5 cm.

-Schober test positive:

    Distraction of less than 10 cm on flexion, measured vertically between spines.

-Thoraco-Iumbar kyphsis develops.

-Recurrent iritis may occur in 10-20% of cases.

-Cardiac features: Aortic incompetence in 2-5 % of cases more often AV conduction defects with prolonged P-R interval.

Investigations:

(1) X-ray

(a)Sacro-iliac joints: Abnormal sacro-iliac joints, Juxta-articular erosion, sclerosis with widening or narrowing, later ankylosis.

(b)Spine: Changes follows sacroilitis:

-Erosions in apophyseal joints

-"Squaring" of vertebral bodies

-Ossification of disc margins and longitudinal ligaments (due to enthesopathies at sites of insertion of fibers of annulus).

-Longitudinal, ligaments calcification with classical "Bamboo" or railway" spine.

(2) ESR: raised in active disease

(3) Latex fixation: negative.

(4) HLA- B 27: present in 90% of cases

Treatment:

a) General: 

- Education of patient.

- Avoid excessive sitting or excessive overuse of back.

b) Physical: Exercises prescribed to:

- Maintain spinal mobility and erect posture

- Breathing exercises to maintain good chest expansion

- Maintain good spinal extensor muscles

- Maintain maximum hip and shoulder joint range.

c) Medical:

- NSAIDs: pain & stiffness usually responds well to indomethacin and naproxyn.

- Sulphasalazine is useful in difficult cases not responding to NSAIDs

d) Radiotherapy:

Is now used  rarely & only in cases when adequate alternative regimen has failed.

e) Surgical:

- Hip arthroplasty for hip ankylosis

- Spinal osteotomy for flexion deformity of the lumbar spine (very rarely).

Chapter 7

SYSTEMIC CONNECTIVE-TISSUE DISEASES

The systemic connective-tissue diseases are a group of chronic inflammatory disorders which predominantly affect women. They involve many different organs and therefore exhibit a wide spectrum of clinical manifestations. Their aetiology is unknown, but it is generally thought to be multifactorial, involving immunological, genetic, environmental and possibly viral factors.

Diseases included under this category are:

1- Rheumatoid arthritis.

2- Systemic lupus erythematosus.

3- Progressive systemic sclerosis.

4- Poly and dermatomyositis.

5- Polyarteritis nodosa.

6- Sjogren's syndrome.

7- Giant cell arteritis.

8- Takayusu's arteritis.

9- Polymyalgia rheumatica

10- Wegener's granulomatosis.

11- Mixed connective-tissue disease.

The systemic connective tissue- diseases are characterized by the following features of autoimmune disease, in addition to clinical similarities:

u High levels of immune globulins in blood and tissues.

v Lymphoid and plasma cell hyperplasia.

w Usually good response to systemic steroids.

Systemic lupus erythematosus will be discussed as one example of systemic connective tissue-diseases.

Systemic Lupus Erythematosus

Definition:

It is a disease of unknown aetiology, commonly affecting many systems of the body. It often presents with an erythematous skin rash and may produce prolonged fever, arthralgia and arthritis, lymphadenopathy, polyserositis (especially pelurisy and pericarditis) and renal, neurological and cardiac damage.

Sex : It affects women more than men in a ratio of 8:1, in the adolescent females and childbearing period.

Race : Negroes more commonly affected than white people.

Aetiology:

l. Immunity:

SLE is thought to occupy a central position among the so-called autoimmune diseases. In these disorders the body appears to build an immune response against some part of itself, there being no recognizable outside antigen. The result is usually a widespread inflammatory reaction.

The markers of autoimmune disease are:

a. High titres of circulating antibodies.

b. Raised serum levels of gamma globulin.

c. Lymphoid and plasma cell hyperplasia.

d. Responsiveness to steroids.

2. Sensitivity:

Despite the absence of a known extrinsic cause of SLE there are several factors that in some cases undoubtedly precipitate on exacerbation. Patients with SLE are commonly light or drug sensitive.

a. Light:

In SLE patients, exposure to sunlight may produce not only exacerbations of the skin eruption but a generalised systemic flare-up of the condition.

b. Drugs:

Hydrallazine (anti-hypertensive) was found to produce an illness characterized by fever, malaise, arthralgia, lupus-like rashes & sometimes LE-cells in the blood.

The symptoms subsided when the drug was stopped. Other drugs such as sulphonamides, anti-epileptic drugs, procainamide and penicillin have all been implicated in the pathogenesis of SLE.

This raised the possibility that lupus might be a form of hypersensitivity to drugs, but it is extremely difficult to prove that these drugs are not merely producers of sensitivity reactions in a patient already suffering from, or developing SLE.

3. Endocrine:

Sex Incidence: About 8 and 9 out of every 10 patients suffering from SLE are females. Although this might suggest an endocrine basis for the disease, no consistent endocrine abnormality has been discovered.

4. Geographical factors:

Most workers agree that the disease is commoner in negros than in white populations. Again, the reasons for these differences, are not known.

Pathology:

SLE may affect most organs and tissues of the body. There are four basic microscopic changes. The affected organs may show one or more of these microscopic changes:

- Fibrinoid change

- Sclerosis of collagen

- Haematoxylin bodies

- Vascular lesions

* Fibrinoid change:

This is an acellular, deeply eosinophillic material result from damage to the ground substance of connective tissue, possibly to fibrin itself. This inflammatory reaction appears to be more intense on the serosal surfaces, such as the pleura.

* Sclerosis of collagen:

As a result of the chronic inflammatory reaction around fibrin the nearby collagen fibres become swollen and altered. Fibroblasts grow with resultant increase in connective tissue formation.

A peculiarly marked example is seen in the spleen, where connective fibrosis encroaches, the splenic arterioles, giving the so-called onion-skin appearance.

* Haematoxylin  Bodies:

There are foci of basophilic staining material, probably consist of desoxyribonucleic add (DNA) released from nuclei damaged by the antibody. The material is possibly identical with that in the LE-cell.

* Vascular Changes:

Widespread lesions in the arterioles and capillaries are responsible for the clinical picture of SLE. Fibrinoid change appears in the intimas, with narrowing of the lumen of the vessel.

Clinical Features:

The widespread tissue involvement in SLE permits an enormous number of possible clinical presentations. The diagnosis depends largely on the recognition that a multi-system disease is present.

(1) Joints:

The most common complaint in SLE is joint pain. Usually, there is a mild flitting arthralgia. True synovitis is common. It tends to be periodic, and rarely causes underlying cartilage destruction. Any joints may be involved, especially the hands, wrists, knees and ankles. Permanent deformity occurs in up to 1/3 of patients. It usually resembles R.A. but radiologically no erosions. A septic necrosis of bone may occur in hip or knee, this is possibly secondary to arteritis.

(2) Skin:

The skin manifestations of SLE are frequent and variable. These include butterfly rash, erythematous rash across the bridge of the nose and the cheeks, photosensitivity, chronic discoid lupus, maculopapular lesions, Alopecia with subcutaneous nodules do occur but are rare.

(3) Heart:

The most common cardiac manifestation of SLE is pericarditis. This may be so mild as to be missed. It occurs in about 1/3 of all patients.

ECG changes consistent with pericarditis are found in the majority of patients.

The clinical picture is usually that of a "dry" painful pericarditis, producing a pericardial friction rub.

Myocardiol disease is frequent in SLE. This commonly produces cardiac enlargement, and signs of cardiac failure.

Causes of heart failure in SLE:

• Myocardiol disease

• Pericardial tamponade

• Anaemia

• Hypertension.

Libman-Sacks endocarditis is usually haemodynamically insignificant murmers are frequently heard in SLE.

(4) Periphiral vascular system:

Raynaud's phenomenon is common. Chronic leg ulcers, recurrent thrombophlebitis, sometimes gangrene.

 (5) Respiratory system:

Pleura: Clinically detectable pleurisy in about g of all cases of

SLE. and most of these develop effusions.

Lungs: Despite the frequency of pathological pneumonitis in this disease, X-ray changes are comparatively uncommon.

An "antibiotic resistant pneumonia" occasionally suggests the diagnosis.

(6) Kidneys:

Proteinuria occurs in about 50% of patients with SLE may lead to full picture of nephrotic syndrome with oedema. In addition, red cells and granular and hyaline casts are found in the urine. The patient may develop, acute renal failure requiring dialysis, or may progress gradually to chronic renal failure and uraemia.

Hypertension is a common and serious complication of SLE. It is secondary to renal damage.

(7) Muscles:

Myositis with muscle pains and tenderness are common. Sometimes, there is wasting and weakness of proximal muscles.

(8) Nervous system:

Any nurological picture may result from SLE.

Attacks of psychosis are probably due to organic brain damage due to cerebral arteritis. Other neurological manifestations include peripheral neuropathy, myelopathy, epilepsy, hemiplegia, vertigo and choreiform movements.

(9) Reticuloendothelial system:

The spleen is sometimes palpable, lymphadenopathy are common.

(10) Eyes:

Association with Sjogren's syndrome and the occurrence of cytoid bodies. These are fluffy white exudate that occur in the nerve fibre layer of the retina and an indistinguishable from the exudates of hypertension or diabetes.

 (11) GIT:

Gastrointestinal symptoms are particularly common and include anorexia, nausea, diarrhoea, gastrointestinal bleeding and abdominal pain and tenderness are due to arteritis, peritonitis, perisplenitis.

Investigations:

ESR: is frequently raised above 100 mm/ hour.

Haematological Findings:

Anaemia is common.

Leucopenia.

Thrombocytopenia.

* Anti nuclear factor test is the most useful screening test for SLE, for it almost invariably positive in active stages of the disease.

A negative ANF test makes the diagnosis of SLE very unlikely.

* LE- cell phenomenon:

A positive ANF test should automatically lead to a search for LE- cells.

It is + ve in about 80% of SLE cases.

* Serum complement: is usually lowered.

Treatment:

General:

Medical:

(1) NSAIDS:

In the mild case or during remission, symptoms may be controlled by NSAIDS. The arthralgia and fever generally respond to NSAIDS.

(2) Chloroquine compounds:

They are effective in controlling skin changes and joint symptoms.

(3) Corticosterouls:

Corticosteroid preparations form the basis of the drug treatment of SLE. Their effects are often dramatic, and they may be life saving.

Indications:

u Major system involvement (renal, carditis)

v Pericardial effusion

w Critical thrombocytopenic purpura or haemolytic anaemia

x Psychotic episode

(4) Immunosuppressive therapy:

They are steroid sparing, i.e. the steroid requirements fall when this form of therapy is added. Cyclophosphamide and azothioprine may be used.

Chapter 8

CRYSTAL DEPOSITION DISEASES

“GOUT AND PYROPHOSPHATE ARTHROPATHY”

In these conditions metabolic product may cause arthropathy in one of two ways:

*The crystals enter the joint space to provoke an acute crystal synovitis, or

*The presence of this crystalline material within the articular cartilage leads to chronic degenerative changes.

In gout, the responsible crystals are urate, while in pseudogout they consist of calcium pyrophosphate.

Gout

Definition: Metabolic disorder of purine metabolism characterized by hyperuricaemia and recurring attacks of arthritis, and in later stages chronic arthritis.

The term gout defines an arthropathy resulting from the deposition of urate crystals in and around joints, tophi formation and a tendency to renal failure.

It is one hazard of a sustained high level of uric acid in the plasma.

The appearance of gout depends on the degree and the duration of plasma uric acid elevation.

Purine Metabolism

Uric acid is produced by the degradation of the purine bases, adenine and guanine “constituents of nucleic acids and nucleotides”, according to the following scheme:

  Adenine                                      Guanine

      ↓                                                ↓  ← Xanthine oxidase

Hypoxanthine -----------------------> Xanthine

                                                        ↓  ← Xanthine oxidase

                                                   Uric acid

In lower mammals this sequence is carried a stage further by the enzyme uricase converting uric acid to allantoin which is then rapidly eliminated through the kidneys. In man, there is no uricase enzyme and ruic acid is the end product of purine metabolism.

Aetiology of hyperuricaemia:

Plasma uric acid level depends on the factors illustrated in this scheme.

The 3 important variables determining the plasma uric acid level are:

u The rate of endogenous purine breakdown.

v The amount of purines in the diet.

w The rate of renal clearance of urate.

The normal range of plasma uric acid level is 4-6 mg/100 ml.

The upper limits of normal in men 6 mg and in women 5 mg/100 ml.

It has been customary to divide gout into primary and secondary forms.

In 2ry gout: refers to cases in which the underlying hyperuricaemia is due mainly to a single well defined cause:

       *Increased turnover of purines such as myeloproliferative disorders or neoplastic disease.

* Reduced renal urate elimination.

* Renal diseases.

* Chronic administration of thiazide diuretics.

In 1ry gout: The hyperuricaemia is the result of multiple interacting variables.

Deposition of urate:

Sustained hyperuricaemia (The critical level is about 7 or 8 mg/l00 ml) leads to deposition of urate in the tissues, particularly in relation to avascular tissues, articular cartilage, the pinna of the ear, the olecranon bursa and tendon generally. The renal parenchyrna is another favourable site.

The result of this orate deposition is seen most dramatically in the joints, where crystals may enter the synovial cavity to provoke an acute synovitis, or the articular cartilage deposits may lead to osteoarthrosis, larger depositis may be clinically obvious as tophi and renal deposits may be associated with nephropathy. Those subjects in whom the urinary urate load is increased (hyperuricosuria) are exposed to the risk of urae stone formation.

Clinical picture:

1ry gout is a disease mainly of post pubertal males and, less often post menopausal females. In practice, over 50 percent of patients with 1ry gout gave positive family history.

Gout usually presents as an attack of acute monarticular crystal synovitis, which settles in a week or 2 weeks to leave a perfectly normal joint. This is followed by further similar attacks at intervals of weeks, months, or even years. After a time tophaceous deposits appear on the pinna of the ears and in relationship to tendons and joints. Affected joints become distored and function is impaired. A minority of gouty patients pass urinary urate claculi and longstanding cases show evidence of renal impairment.

The acute attack

First attack of gout usually affects the metatarsophalangeal joint of the big toe (Podagra). This site may be favoured because of the trauma to which it is subjected. Subsequent attack may return to the same joint. The opposite joint, or else where. But the hips and shoulders tend to be spared and are never affected in the first attack.

The attack is often dramatically acute pain, tenderness and swelling appears and over a few hours until the joint is tensely swollen, warm, red and dry (contrasting with the moist skin over the acute rheumatic fever or septic joint). There is often a systemic reaction with malaise, fever, tachycardia. Raised sedimentation rate and leucocytosis. Untreated the severe pain persists for a few days, then gradually subsides over a week or two, to leave a perfectly normal joint.

Pathogenesis of acute urate arthropathy

Acute gouty arthritis is an inflammatory response to the presence of microcrystalline urate within the synovial fluid. Whether these crystals are precipitated in the fluid de novo or arise from ruptured microtophi is uncertain.

During an acute attack, urate crystals are phagocytosed by neutrophils which then die and rupture, releasing the enzymes contained within their lysosomes to act as the chemical mediators of the inflammation.

Chronic gouty arthropathy

Urate deposits appear within the joint cartilage and bone, these deposits interfere with joint function both by the destruction of the joint, bearing surfaces and by mechanically obstructing the joint mobility.

Clinically: chronic gouty joints present the features of osteoarthrosis in association with tophaceous swelling in and around the articulation.

Tophi:

The presence of tophi is a measure of the severity of gout. The patients who develops tophi within a few years of his first attack of arthritis is likely, if untreated to progress, tophi eventually present on the helix of the ear. Joint cartilage, bursae and tendon sheaths are other favoured sites.

Urate urolithiasis:

Urate urolithiasis occurs in about 20% of gouty subjects. The formation of urate stones is favoured by:

* High urinary urate output.

* Concentrated urine.

* Highly acidic urine.

Pure urate calculi are radiolucent on x-ray in contrast to calcium containing stones.

Gouty nephropathy is characterized by:

* Proteinuria

* Impaired concentration

* Decreased clearance values

* Finally nitrogen retention and hypertension. Directly or indirectly, renal diseases is the most important cause of death in gouty subjects.

Investigations

* Plasma urate level: The upper limit of normal is usually accepted as 6 mg/100 ml for men and 5 mg/lO0 ml for premenopausal women.

The upper limit of normal for the total 24 hours urinary urate is about 600 mg.

* Examination of synovial fluid for crystals:

The most positive method of diagnosis of gout is to identify urate crystals within synovial fluid from an affected joint by the use of the polarised light microscope.

*X.ray in gout:

Uric acid and urate salts are translucent to x-ray.

Tophaceous deposits therefore appear as clear areas.

Small tophaceous deposits in bone may produce punched out areas.

Diagnosis:

* The occurrence of podagra or typically acute arthritis in other sites, in a patient with a raised plasma uric acid, provides presumptive evidence of gout.

* Identification of urate cystals in synovial fluid, in biopsy material from a joint or in a material from tophus.

* A positive family history.

* The response of an acute attack of arthritis to colchicine is regarded as confirmatory evidence of diagnosis of gout because colchicine is specific for gout.

Treatment:

Aims:

* Preventing attacks of crystal synovitis, or terminating them once they have started.

* To lower the plasma uric acid level.

Treatment of acute attack:

u Colchicine tablets (0.5 mg every 2 hours by mouth), until either the attack cleared or toxic effects in the form of vomiting or diarrhea occur. Colchicine inhibits the phagocytic activity of leucocytes thus breaking the pathological cycle in, crystal synovitis. Its effect in gout is sufficiently specific for a clear cut response to be regarded as confirmatory evidence of this diagnosis.

v Non steroidal anti-inflammatory drugs: Indomethacin in large initial doses (150 mg daily), then reduced over the next few days, seem to be more effective than colchicine.

w If the affected joint is accessible to drainage by aspiration, then this, combined with a local corticosteroids injections, is the most certain and rapid method of terminating the acute attack.

Prophylaxis between the attacks:

Colchicine in doses of 0.5 to 1.5 mg daily reduces the frequency of acute attacks.

Reduction of plasma uric acid level: Indications for such treatment are:

u The persistence of acute attack

v The development of tophi or

w A plasma uric acid level consistently over 8 mg/l00 ml. 2 types of drug therapy are capable of reducing the plasma uric acid level:

a- Uricosuric drugs

b- Allopurinol group

a. The uricosuric drugs: Act by paralysing renal tubular transport of urate, which effectively prevents urate being either reabsorbed or secreted in the proximal tubule and the full filtered load is available to pass on for elimination in the urine. The increased urinary urate load represents an added risk of stone formation. This hazard is minimized by reducing the acidity of the urine and increasing fluid intake. Salicylates should be avoided by patients on uricosuric drugs:

* Probencid (Benemid) 1-2 g/day.

* Sulphin pyrazone (Anturan) 200-400 mg/day

b. Allopurinol drug: is an inhibitor for the enzyme xanthine oxidase and reduce the production of urate.

Dose: 200-600 mg/day.

The present policy is to use one of the uricosuric durgs initially in the uncomplicted case, reserving allopurinol for the following circumstances:

* Failure of adequate control by uricosuric drugs.

* An added liability to urolithiasis (a history of passing stones, renal colic, haematuria or a very high urinary urate output).

* the presence of renal failure.

* In severe case, difficult to control, uricosuric drugs and allopurinol therapy can usefully be combined. It is in this situation that the prescription of a low purine diet is necessary.

* Allopurinol finds a special use in the treatment of leukaemias.

* Prevention of urate urolithiasis:

- Ample fluid intake.

- Alkalies such as Na bicarbonate.

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